doi: 10.1161/CIRCULATIONAHA.105.604991
(Circulation. 2006;114:1315-1320.)
© 2006 American Heart Association, Inc.
Controversies in Cardiovascular Medicine |
The Argument Against the Appropriateness of Over-the-Counter Statins
From The Heart Research Institute and the Department of Medicine, University of Sydney, Sydney (P.J.B., K.-A.R.), and the Department of Medicine, University of Melbourne, Melbourne (K.-A.R.), Australia.
Correspondence to Professor Philip Barter, The Heart Research Institute, 145 Missenden Rd, Camperdown, NSW 2050, Australia. E-mail barterp{at}hri.org.au
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Introduction |
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 Top Introduction Balance Between Benefits and...Failure to Achieve Recommended...Failure to Address a...ConclusionsReferences |
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The availability of statins has revolutionized the management of patients at high risk of having a cardiovascular (CV) event. Statins reduce the risk of future CV events in virtually everyone in whom they are used. The benefit is apparent in those with and without manifest CV disease and is independent of age, gender, and the presence of disorders such as hypertension and diabetes. The benefit also is independent of the baseline level of low-density lipoprotein (LDL) cholesterol. In fact, to date, there is no group (with the possible exception of those with end-stage renal disease) in whom CV risk is not reduced by statin use. Furthermore, the available members of this drug class are well tolerated and have an excellent safety record, with serious adverse effects such as myopathy and liver damage occurring in only a small percentage of people taking these agents.
Response by Gotto p 1320
On the basis of the available evidence base, most current guidelines recommend the use of statins in all high-risk people, with high risk being variously defined as those either with existing CV disease or with a calculated 5-year risk that is comparable to that in people with manifest disease.
Given the evidence of efficacy and safety, it has been suggested that statins should be provided over the counter (OTC) in pharmacies without the need for a prescription to make them accessible to a much wider group of people. This approach has already been adopted in the United Kingdom, where low-dose (10 mg) simvastatin is now available OTC. The question arises: Is it desirable to make statins available OTC?
This article argues against making statins available OTC on 3 grounds: (1) The risk of adverse effects may no longer be outweighed by the benefits if statins are used in people at low CV risk; (2) high-risk people may not achieve the low LDL targets shown to be desirable to maximize risk reduction; and (3) other lipid abnormalities such as a low high-density lipoprotein (HDL) cholesterol may not be identified or treated.
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Balance Between Benefits and Adverse Effects |
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TopIntroductionBalance Between Benefits and...Failure to Achieve Recommended...Failure to Address a...ConclusionsReferences |
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There is no such thing as a drug without some serious adverse effects in at least some people. However, if the incidence of adverse effects is low relative to the potential benefit provided by the drug (high benefit-to-risk ratio), the possibility of even serious adverse events should not (and generally does not) prevent the drug from being used. Clearly, the benefit-to-risk ratio associated with statin use is high in someone whose risk of having a CV event also is high. In those individuals at much lower risk, on the other hand, the benefit-to-risk ratio associated with statin use is also lower; indeed, in low-risk people, it is possible that statin-induced adverse effects may exceed the potential benefits. This is especially pertinent when we consider that, once an individual has begun to use them, statins are likely to be used for many years.
The best-known serious adverse effect of statins is a myopathy that, in some people, may result in potentially fatal rhabdomyolysis. Significant myopathy is relatively uncommon, occurring in <0.5% of patients taking these agents.1 It is dose dependent and is a major factor in determining what should be the highest recommended dose of each member of the class. Progression of myopathy to the potentially fatal condition of rhabdomyolysis is a rare occurrence, with a reported frequency of 1 in 30 000 to 100 000 patient-years of exposure.1 Rhabdomyolysis has been observed with all statins, although its frequency varies with the different members of the class.2,3 The higher relative frequency of rhabdomyolysis associated with use of cerivastatin4 led to this agent being withdrawn from the market.
There are well-documented circumstances in which the risk of rhabdomyolysis in people taking statins is increased5–9 (Table). The best known of these instances relates to the potential of statins to interact adversely when coadministered with fibrates5,6 and macrolide antibiotics such as erythromycin.7 The risk of serious myopathy associated with the use of statins also is increased in people taking cyclosporine after renal or heart transplant.8 Although it is most unlikely that a transplant patient would use OTC statins, there is a real danger that someone taking OTC statins could inadvertently be prescribed an agent such as erythromycin. The possibility of this occurring in someone at low risk of having a CV event creates a setting in which the benefit-to-risk ratio may be unacceptably low.
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Adverse effects of statins also are greater in the elderly,9 in whom the potential dangers of OTC statins may be especially high. The fact that many elderly people are already taking many other medications may add to the risk of serious adverse effects associated with unmonitored use of statins in such people.
The most common argument used to support the availability of OTC statins is that doing so will make these agents accessible to a much wider range of people than is recommended by current guidelines. It is argued that these agents are so safe and so effective that there is no justification for limiting them only to high-risk people. However, before accepting this proposition, we should consider just how great the potential benefits are of using statins in someone whose CV risk is low.
Consider someone whose 5-year CV risk is 2%. Treatment with, for example, 20 mg simvastatin would be predicted to reduce the concentration of LDL cholesterol by 
40 mg/dL. According to a recent meta-analysis,10 an LDL cholesterol reduction of this magnitude would translate into an 20% reduction in CV risk, thus converting the 5-year CV risk in this person from 2% to 1.6%. The risk of a serious adverse event associated with the unmonitored use of a statin in such a person may well exceed this small benefit. The reality is that it is impossible to calculate either the benefit-to-risk ratio or the cost-effectiveness of OTC statin in people whose CV risk is low. If, however, CV risk is high, it is essential that therapy be closely monitored to ensure that recommended LDL cholesterol targets are achieved.
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Failure to Achieve Recommended LDL Targets |
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TopIntroductionBalance Between Benefits and...Failure to Achieve Recommended...Failure to Address a...ConclusionsReferences |
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A direct involvement of LDL cholesterol in the development and progression of atherosclerotic cardiovascular disease is one of the best-proven cases in modern medicine. A strong, positive relationship between the concentration of LDL cholesterol and the future risk of CV events has been observed in many large-scale population studies,11,12 and the benefits of reducing LDL cholesterol levels have been proved beyond doubt in intervention studies.10
The CV risk reduction associated with statin use is a direct function of both the magnitude of the reduction in concentration of LDL cholesterol10 (Figure 1) and the level of LDL cholesterol achieved by the treatment13 (Figure 2). There is growing consensus that if a statin is indicated, it should be used in a dose sufficient to achieve levels of LDL cholesterol that are very much lower than were previously considered to be ideal.14 Such targets are most unlikely to be achieved in people taking the low doses of statins that are likely to be available OTC.
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The evidence base in support of aggressive LDL cholesterol lowering is huge. It includes studies that have involved >100 000 people in long-term, large-scale, controlled clinical trials. These trials have been conducted in settings of primary and secondary prevention, in men and women spanning a wide range of ages, in diabetics and nondiabetics, in those with and without hypertension, and in people with a wide range of baseline levels of LDL cholesterol.
A recent meta-analysis of data from 90 056 participants in 14 randomized trials of statins was reported by the Cholesterol Treatment Trialists’ collaborators.10 This analysis was motivated by the fact that, in isolation, none of the individual trials had sufficient power to assess the precise relationship between the magnitude of LDL lowering and the extent of CV event reduction. The database for the meta-analysis included 8186 deaths and 14 348 major CV events. The reductions in LDL cholesterol in these trials ranged from 13 to 68 mg/dL. Overall, for each 40-mg/dL reduction in LDL cholesterol, there was a 12% reduction in all-cause mortality, a 23% reduction in myocardial infarction or coronary death, a 24% reduction in the need for coronary revascularization, and a 17% reduction in fatal or nonfatal stroke. All of these reductions were statistically highly significant. The reduction in major vascular events was predicted by the absolute reduction in LDL cholesterol achieved. It was concluded on the basis of this meta-analysis that prolonged statin treatment with substantial LDL cholesterol reductions should be considered in all patients at high risk of any type of major vascular event.
The meta-analysis established beyond reasonable doubt that CV event reduction is proportional to the magnitude of the LDL lowering.10 There is also growing evidence that the actual level of LDL cholesterol achieved during treatment with statins is predictive of CV events. This was best shown in the recently reported Treating to New Targets (TNT) trial.13 This trial was designed to assess the efficacy and safety of treating people with stable coronary heart disease (CHD) to LDL cholesterol levels significantly below 100 mg/dL. A total of 10 001 patients with clinically manifest CHD were randomized to double-blind therapy with atorvastatin 10 or 80 mg/d and followed up for a median of 4.9 years. The primary end point was a major CV event defined as CHD death, nonfatal non–procedure-related myocardial infarction, resuscitated cardiac arrest, and fatal or nonfatal stroke.
The mean LDL cholesterol level achieved during treatment was 77 mg/dL with atorvastatin 80 mg and 101 mg/dL with atorvastatin 10 mg. A primary event was recorded in 434 patients (8.7%) in the group receiving atorvastatin 80 mg and in 548 patients (10.9%) in the 10-mg group. This 22% reduction in the risk of major CV events in the 80-mg group was statistically highly significant (P<0.001). There was also a significant reduction in stroke (fatal plus nonfatal) in the 80-mg group compared with the 10-mg group. Stroke occurred in 117 patients (2.3%) receiving atorvastatin 80 mg and 155 patients (3.1%) receiving atorvastatin 10 mg, representing a 25% reduction (P<0.001) in the 80-mg group. There was no difference in total mortality between the 2 groups: 284 patients (5.7%) died in the group receiving atorvastatin 80 mg and 282 (5.6%) in the group receiving atorvastatin 10 mg, possibly reflecting the fact that the mortality in this trial was considerably lower in both the 10-mg and 80-mg groups than had been reported in any of the previously published secondary prevention trials with statins.
The TNT trial added to a mounting body of evidence that lowering LDL cholesterol to levels well below the previously recommended target of 100 mg/dL results in a clinically and statistically significant additional reduction in the risk of future CV events.
A similar conclusion was drawn from the results of the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) trial, in which the effects of low-dose simvastatin were compared with high-dose atorvastatin.15 The low-dose simvastatin group achieved an LDL cholesterol of 104 mg/dL compared with 84 mg/dL in the high-dose atorvastatin group. The primary end point of the TNT trial (major CV events, defined as the combination of CHD death, nonfatal non–procedure-related myocardial infarction, resuscitated cardiac arrest, and fatal or nonfatal stroke) was prespecified as a secondary end point in the IDEAL study. Consistent with the results in TNT, the combined end point of major CV events in IDEAL was 13% lower (P=0.02) in the aggressively treated group, which achieved an LDL cholesterol level of 81 mg/dL, than in the less aggressively treated group, in which the LDL cholesterol was 104 mg/dL.
The case in favor of achieving very low levels of LDL cholesterol is now overwhelming. To achieve these newly recommended LDL cholesterol targets in many people, it is necessary to use the highest doses of the most effective statins. Such levels are most unlikely to be achieved by the unmonitored use of low doses of statins purchased OTC. The unmonitored use of OTC statins also will make it most unlikely that other lipid abnormalities such as a low level of HDL cholesterol will be identified and treated.
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Failure to Address a Low Level of HDL Cholesterol |
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TopIntroductionBalance Between Benefits and...Failure to Achieve Recommended...Failure to Address a...ConclusionsReferences |
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It has been known for many years that the concentration of HDL cholesterol correlates inversely with CV risk11,16–18 (Figure 3). There is a real danger that making statins available OTC will result in a failure to identify and treat people with low levels of HDL cholesterol.
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The particular importance of identifying low levels of HDL cholesterol in people treated with a statin is highlighted by the observation (see below) that statins do not eliminate the increased CV risk that is attributable to the low HDL cholesterol level. Indeed, there is growing consensus that cholesterol-related CV risk needs to be attacked simultaneously on 2 fronts: by reducing the level of LDL cholesterol with a statin while raising HDL cholesterol with niacin or a fibrate. This view has been strengthened by the results of the INTERHEART (Effect of Potentially Modifiable Risk Factors Associated With Myocardial Infarction in 52 Countries) study19 in which the ratio of apolipoprotein B to apolipoprotein A-I (reflecting the ratio of LDL to HDL) was of enormous power in predicting future myocardial infarction in a large cohort of subjects of widely differing ethnic origin.
A low level of HDL cholesterol is a well-recognized component of the dyslipidemia associated with insulin-resistant states such as type 2 diabetes and the metabolic syndrome.20,21 The prevalence of these disorders (and the associated low HDL cholesterol) is increasing alarmingly, largely as a consequence of a worldwide epidemic of abdominal obesity.22 In people with these insulin-resistant states, it may be argued that raising the level of HDL cholesterol is even more important than lowering the level of LDL cholesterol. Ideally, both LDL and HDL should be targeted.
Statins reduce CV risk in virtually all groups of people in whom they have been studied. This includes people with low levels of HDL cholesterol. However, although a statin will reduce CV risk in those with low HDL cholesterol levels, the HDL cholesterol level before statin therapy is started remains predictive of CV events even after statin therapy has been initiated. This observation has been made in several large-scale statin trials conducted in both a primary and secondary prevention setting.
The inability of statins to eliminate the CV risk associated with low levels of HDL cholesterol was apparent in a primary prevention setting with pravastatin in the West of Scotland Coronary Prevention Study (WOSCOPS)23 and in a secondary prevention setting with pravastatin in the pooled analysis of the Long-Term Intervention With Pravastatin in Ischemic Disease (LIPID) and the Cholesterol and Recurrent Events (CARE) trials24 and with simvastatin in the Heart Protection Study (HPS).25 In all of these trials, treatment with a statin largely eliminated the influence of baseline LDL cholesterol as a predictor of coronary events, regardless of whether the HDL cholesterol was high or low. In each of these studies, however, the baseline level of HDL cholesterol remained as predictive of events in the statin-treated group as in the placebo group (Figure 4).
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Thus, a low level of HDL cholesterol is an important target for therapy to reduce CV risk; a low level of HDL cholesterol is becoming increasingly common; and it has been a consistent finding that a low level of HDL cholesterol before statin therapy is begun remains predictive of CV events even after statin therapy has been initiated. Therefore, it is apparent that to maximize risk reduction, a low level of HDL cholesterol requires therapy beyond a statin. Such action is most unlikely to be initiated in someone taking statins OTC.
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Conclusions |
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TopIntroductionBalance Between Benefits and...Failure to Achieve Recommended...Failure to Address a...ConclusionsReferences |
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There is no doubt that statins reduce CV risk in all people who take them. When CV risk is high, the evidence supports aggressive treatment to achieve low LDL cholesterol targets. These targets are most unlikely to be attained by the use of OTC statins. Although it may be argued that these aggressive LDL cholesterol targets are less important in people whose CV risk is lower, it also is apparent that the absolute risk reduction in such people also will be much lower, with the possibility arising that serious adverse events may exceed the benefits. Thus, there is a strong case against the use of OTC statins in both high-risk and low-risk people. In addition, the unmonitored use of OTC statins inevitably will lead to an increase in the adverse effects resulting from the adverse interaction of statins with other agents. Finally, making statins available OTC will reduce the likelihood of identifying people at high risk because of a low level of HDL cholesterol. Given that a low HDL cholesterol remains predictive of risk while statins are taken, it follows that use of OTC statins will leave many people at an unacceptably high risk of having a future CV event.
A question was posed at the beginning of this article: Is it desirable to make statins available OTC? Clearly, the answer is no.
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Acknowledgments |
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Source of Funding
Dr Rye is a National Heart Foundation of Australia Principal Research Fellow.
Disclosures
Drs Barter and Rye have received research grants from Pfizer Pharmaceutical; served on the speakers’ bureau for and received honoraria from Pfizer, AstraZeneca, Abbott, and Fournier; and worked as a consultant or on the advisory board for Prizer, AstraZeneca, and Abbott.
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References |
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TopIntroductionBalance Between Benefits and...Failure to Achieve Recommended...Failure to Address a...ConclusionsReferences |
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1. Mukhtar RY, Reckless JP. Statin-induced myositis: a commonly encountered or rare side effect? Curr Opin Lipidol. 2005; 16: 640–647.[Medline] [Order article via Infotrieve]
2. Ucar M, Mjorndal T, Dahlqvist R. HMG-CoA reductase inhibitors and myotoxicity. Drug Saf. 2000; 22: 441–457.[CrossRef][Medline] [Order article via Infotrieve]
3. Omar MA, Wilson JP. FDA adverse event reports on statin-associated rhabdomyolysis. Ann Pharmacother. 2002; 36: 288–295.[Abstract]
4. Jamal SM, Eisenberg MJ, Christopoulos S. Rhabdomyolysis associated with hydroxymethylglutaryl-coenzyme A reductase inhibitors. Am Heart J. 2004; 147: 956–965.[CrossRef][Medline] [Order article via Infotrieve]
5. Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate + statin versus gemfibrozil + any statin. Am J Cardiol. 2005; 95: 120–122.[CrossRef][Medline] [Order article via Infotrieve]
6. Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA. 2003; 289: 1681–1690.
7. Lee AJ, Maddix DS. Rhabdomyolysis secondary to a drug interaction between simvastatin and clarithromycin. Ann Pharmacother. 2001; 35: 26–31.[Abstract]
8. Ballantyne CM, Corsini A, Davidson MH, Holdaas H, Jacobson TA, Leitersdorf E, Marz W, Reckless JP, Stein EA. Risk for myopathy with statin therapy in high-risk patients. Arch Intern Med. 2003; 163: 553–564.
9. Foody JM, Krumholz HM. Are statins indicated for the primary prevention of CAD in octogenarians? Antagonist viewpoint. Am J Geriatr Cardiol. 2003; 12: 357–360.[Medline] [Order article via Infotrieve]
10. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R, for the Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005; 366: 1267–1278.[CrossRef][Medline] [Order article via Infotrieve]
11. Shaten BJ, Kuller LH, Neaton JD. Association between baseline risk factors, cigarette smoking, and CHD mortality after 10.5 years: MRFIT Research Group. Prev Med. 1991; 20: 655–659.[CrossRef][Medline] [Order article via Infotrieve]
12. Castelli WP, Anderson K, Wilson PW, Levy D. Lipids and risk of coronary heart disease: the Framingham Study. Ann Epidemiol. 1992; 2: 23–28.[Medline] [Order article via Infotrieve]
13. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK, for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005; 352: 1425–1435.
14. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ, for the National Heart, Lung, and Blood Institute, American College of Cardiology Foundation, and American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004; 110: 227–239.
15. Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I, Larsen ML, Bendiksen FS, Lindahl C, Szarek M, Tsai J, for the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 2005; 294: 2437–2445.
16. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease: the Framingham Study. Am J Med. 1977; 62: 707–714.[CrossRef][Medline] [Order article via Infotrieve]
17. Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD, Jacobs DR Jr, Bangdiwala S, Tyroler HA. High-density lipoprotein cholesterol and cardiovascular disease: four prospective American studies. Circulation. 1989; 79: 8–15.
18. Assmann G, Schulte H, von Eckardstein A, Huang Y. High-density lipoprotein cholesterol as a predictor of coronary heart disease risk: the PROCAM experience and pathophysiological implications for reverse cholesterol transport. Atherosclerosis. 1996; 124 (suppl): S11–S20.[CrossRef][Medline] [Order article via Infotrieve]
19. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, Lisheng L, for the INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004; 364: 937–952.[CrossRef][Medline] [Order article via Infotrieve]
20. Ginsberg HN. Lipoprotein physiology in nondiabetic and diabetic states: relationship to atherogenesis. Diabetes Care. 1991; 14: 839–855.[Abstract]
21. Barter P. Metabolic abnormalities: high-density lipoproteins. Endocrinol Metab Clin North Am. 2004; 33: 393–403.[CrossRef][Medline] [Order article via Infotrieve]
22. Zimmet P. The burden of type 2 diabetes: are we doing enough? Diabetes Metab. 2003; 29: 6S9–6S18.[Medline] [Order article via Infotrieve]
23. West of Scotland Coronary Prevention Study Group. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation. 1998; 97: 1440–1445.
24. Sacks FM, Tonkin AM, Shepherd J, Braunwald E, Cobbe S, Hawkins CM, Keech A, Packard C, Simes J, Byington R, Furberg CD. Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors: the Prospective Pravastatin Pooling Project. Circulation. 2000; 102: 1893–1900.
25. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002; 360: 7–22.[CrossRef][Medline] [Order article via Infotrieve]
26. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA. 2002; 288: 2998–3007.
27. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS: Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998; 279: 1615–1622.
28. Long-Term Intervention With Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998; 339: 1349–1357.
29. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels: Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996; 335: 1001–1019.
30. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E, Ostergren J, for the ASCOT Investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003; 361: 1149–1158.[CrossRef][Medline] [Order article via Infotrieve]
31. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH, for the CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004; 364: 685–696.[CrossRef][Medline] [Order article via Infotrieve]
32. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia: West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995; 333: 1301–1307.
33. Scandinavian Simvastatin Survival Study Investigators. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994; 344: 1383–1389.[CrossRef][Medline] [Order article via Infotrieve]
34. Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L, Gurwitz JH, Chan KA, Goodman MJ, Platt R. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA. 2004; 292: 2585–2590.
35. Bellosta S, Paoletti R, Corsini A. Safety of statins: focus on clinical pharmacokinetics and drug interactions. Circulation. 2004; 109 (suppl I): III-50–III-57.[Medline] [Order article via Infotrieve]
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Footnotes |
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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